Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 in nonhuman primates following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination

Abstract

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy

“…Thus, our data add to the growing body of evidence suggesting absence of an ADE mechanism during SARS-CoV-2 infection with a protective rather than pathogenic role for Fc (Schafer et al, 2021;Winkler et al, 2021). However, as the expression pattern of murine FcγRs on immune cells differs from that in humans, additional investigations, in other animal models, are required to confirm definitive absence of ADE in SARS-CoV-2 infection (Gorman et al, 2021).…”

Divergent trajectories of antiviral memory after SARS-Cov-2 infection

“…Previous studies have shown that early distinct antigenic targets and qualitative features of SARS-CoV-2-specific antibodies are associated with disease trajectory 44,45 , whilst multifunctional antibody responses, and particularly ADCD and ADNP, following adoptive transfer of IgG from convalescent rhesus macaques have been shown to contribute to protection from SARS-CoV-2 challenge 46 . Furthermore, vaccine-induced Fc-mediated polyfunctionality has been observed following administration of efficacious vaccines in both macaque and human studies 31,47 . While the capacity of Fc receptor binding appears to be lower in convalescent individuals against VOCs, evidence is emerging of maintenance of vaccine-induced Fc-functional antibody properties against VOCs supporting resilience of humoral immunity against VOCs independent of neutralisation 48 .…”

Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif

“…Thus, if herd immunity is not achieved or if antigenic drift of SARS-CoV-2 necessitates reformulation of current vaccines, it may present an opportunity to incorporate immunogens based on emerging coronaviruses identified through surveillance (20); importantly, based on the data presented here, such incorporation would not be at the detriment of neutralizing activity against SARS-CoV-2. Assessing in vivo protection efficacy of this vaccine regimen against SARS-CoV-2, in context of preexisting immunity to SARS-CoV-2, is hindered by the observation that a single SARS-CoV-2 spike immunization alone provides notable in vivo protection (59).…”